OBJECTIVES: Renal cell carcinoma (RCC) is the most lethal urologic malignancy with increasing incidence worldwide. The conventional treatment strategies for advanced or recurrent RCC are not efficient and show considerable toxicities. Adoptive cell transfer (ACT) has become a promising treatment option for multiple cancers, particularly in combination with other therapeutic approaches. ACT often utilizes extensively in vitro expanded tumor-infiltrating lymphocytes (TILs). However, TILs are a very heterogeneous mix of cell populations and only those populations that have a cytotoxic and migratory potential are thought to deliver a therapeutic impact in ACT. The identification and localization of these therapeutically potent populations are therefore needed. METHODS AND MATERIALS: A total number of 57 tissue samples from 19 RCC patients who underwent radical nephrectomy was analyzed. The tissue samples were obtained from the tumor, peritumoral tissue, and the adjacent healthy renal tissue. The tissues were sliced, enzymatically dissociated into single cell suspensions and the obtained cells further analyzed by flow cytometry for the expression of markers of lymphocyte cytotoxicity - TRAIL and FasL, and a surrogate marker of lymphocyte migratory activity - PECAM-1. The analyzed data were next correlated with the clinical and histopathological data. RESULTS: Non-clear cell RCC (non-ccRCC) tumors showed a significantly decreased tumor infiltration with TRAIL+FasL+ NK cells but elevated infiltration with FasL+PECAM-1+ T cells as compared with clear cell RCC (ccRCC) tumors. Further analyses revealed that the peritumoral tissue of ccRCC patients is a reservoir of TRAIL+FasL+, TRAIL+PECAM-1+, or FasL+PECAM-1+ NK and T cells. CONCLUSIONS: The cytotoxic/migratory lymphocytes were identified in tumors of ccRCC patients. These lymphocytes became excluded from the tumor and accumulated in the patient's peritumoral tissue.
- MeSH
- Platelet Endothelial Cell Adhesion Molecule-1 metabolism MeSH
- Killer Cells, Natural immunology metabolism MeSH
- Cytotoxicity, Immunologic MeSH
- Carcinoma, Renal Cell immunology pathology surgery MeSH
- Kidney cytology immunology pathology surgery MeSH
- Middle Aged MeSH
- Humans MeSH
- Fas Ligand Protein metabolism MeSH
- Kidney Neoplasms immunology pathology surgery MeSH
- Nephrectomy MeSH
- TNF-Related Apoptosis-Inducing Ligand metabolism MeSH
- Flow Cytometry MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Cell Separation MeSH
- T-Lymphocytes immunology metabolism MeSH
- Lymphocytes, Tumor-Infiltrating immunology metabolism MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Observational Study MeSH
- Research Support, Non-U.S. Gov't MeSH
BACKGROUND: Human papillomavirus (HPV) type 16 infection is one of the most important etiological agents of oropharyngeal squamous cell carcinoma. Patients with HPV-associated carcinomas of the head and neck were reported to have a better clinical outcome than patients with HPV-negative tumors. Because HPV16 E6 and E7 oncoproteins are highly immunogenic and constitutively expressed, HPV-specific T cell immunity may play the key role in improving the prognosis of these patients. METHODS: Tumor-derived T cells were expanded in high levels of IL-2 and stimulated with HPV16 E6/E7 peptides in the presence or absence of anti-PD-1 monoclonal antibody nivolumab and soluble Tim-3. RESULTS: HPV16-specific tumor-infiltrating T cells were present in 73.1% of HPV-associated oropharyngeal tumors. HPV16 specific CD8+ TILs were able to produce IFNγ upon specific stimulation and predominantly expressed PD-1 but not Tim-3. Specific IFNγ production was further enhanced after a blockade of both PD-1 and Tim-3 pathways but not after a PD-1 blockade alone. Additionally, the specific stimulation of anti-HPV16 CD8+ T cells suppressed Tim-3 upregulation after the PD-1 blockade. CONCLUSION: Our data provide the rationale for combination cancer immunotherapy approaches, including the dual blockade of PD-1 and Tim-3 and, potentially, the use of HPV16-directed therapeutic vaccines.
- MeSH
- Programmed Cell Death 1 Receptor antagonists & inhibitors metabolism MeSH
- Hepatitis A Virus Cellular Receptor 2 metabolism MeSH
- CD8-Positive T-Lymphocytes immunology MeSH
- Cytokines biosynthesis MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Human papillomavirus 16 isolation & purification MeSH
- Oropharyngeal Neoplasms drug therapy immunology metabolism virology MeSH
- Nivolumab therapeutic use MeSH
- Antineoplastic Agents, Immunological therapeutic use MeSH
- Aged MeSH
- Lymphocytes, Tumor-Infiltrating immunology MeSH
- Tumor Escape MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Dlaždicobuněčné karcinomy hlavy a krku patří stále k onemocněním s velmi nejistou prognózou. Úspěšnost léčby se v posledních letech příliš nemění, přestože pokrok v terapeutických metodách je značný a rozšiřují se i znalosti o biologické povaze nádorových buněk a vztahu k hostiteli. Nádory orofaryngu, vzniklé na podkladě infekce virem lidského papillomaviru (HPV), se odlišují klinickou manifestací, vývojem i prognózou. Do značné míry je tento fakt vysvětlitelný i rozdíly v imunitní odpovědi pacientů obou skupin. Shrnutí rozdílností imunitního systému pacientů s HPV asociovanými nádory hlavy a krku a nádory vzniklými na podkladě jiné etiologie je předmětem tohoto sdělení.
Squamous cell carcinoma of head and neck still belongs to the diseases with very uncertain prognosis. Effectivity of the treatment remains approximately the same during the recent years despite the considerable progress in therapeutic methods and increasing level of knowledge about the biology of the tumor cells in relation with the host. Oropharyngeal cancers associated with the human papillomavirus (HPV) infection are different in clinical manifestation, course and prognosis. One may speculate that this fact can be explained by the distinction of the immune system. The main characteristics of immune response of HPV associated tumors and cancers with the different etiology are summarized in the text.
In order to select a suitable combination of cancer cell lines as an appropriate source of antigens for dendritic cell-based immunotherapy of ovarian cancer, we analyzed the expression level of 21 tumor associated antigens (BIRC5, CA125, CEA, DDX43, EPCAM, FOLR1, Her-2/neu, MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A10, MAGE-A12, MUC-1, NY-ESO-1, PRAME, p53, TPBG, TRT, WT1) in 4 established ovarian cancer cell lines and in primary tumor cells isolated from the high-grade serous epithelial ovarian cancer tissue. More than 90% of tumor samples expressed very high levels of CA125, FOLR1, EPCAM and MUC-1 and elevated levels of Her-2/neu, similarly to OVCAR-3 cell line. The combination of OV-90 and OVCAR-3 cell lines showed the highest overlap with patients' samples in the TAA expression profile.
- MeSH
- Antigens, Neoplasm analysis MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Biomarkers, Tumor analysis MeSH
- Cell Line, Tumor MeSH
- Tumor Cells, Cultured MeSH
- Neoplasms, Glandular and Epithelial immunology MeSH
- Ovarian Neoplasms immunology MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Gene Expression Profiling MeSH
- Transcriptome * MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
V posledních několika letech se významně změnil pohled na biologickou podstatu nádorů v oblasti hlavy a krku. Klasickými prokázanými rizikovými faktory nádorů v oblasti hlavy a krku jsou kouření a konzumace alkoholu, resp. jejich kombinace. Pacienti s nádory vzniklými na podkladě této etiologie se pohybují ve vyšších věkových skupinách, nejčastěji v pátém a šestém decéniu. Dále byla v posledních přibližně 15 letech prokázána souvislost s infekcí lidským papillomavirem (HPV), který je dnes považován za jeden z nejvýznamnějších rizikových faktorů, zejména pro karcinom orofaryngu. HPV pozitivní nádory orofaryngu jsou spojeny s významně lepší prognózou onemocnění. Výzkumná i klinická data ukazují, že HPV pozitivní a negativní nádory lze v mnoha ohledech považovat za dvě rozdílné entity a dosud není zcela objasněno, jaké faktory jsou klíčové pro lepší prognózu HPV pozitivní nádorů. Jedním z důležitých faktorů, který se podílí na rozdílné prognóze, může být charakter imunitní reakce. Tento článek shrnuje současné poznatky o různých aspektech protinádorové imunitní reakce u HPV pozitivních a negativních nádorů. Současné studie udávají, že téměř u všech HPV pozitivních pacientů byly detekovány významné počty HPV specifických T lymfocytů, v nádorové tkáni. I navzdory tomu však dochází k rozvoji nádoru, což může být způsobeno abnormalitami v antigenní prezentaci, dysfunkcemi T lymfocytů či přítomností různých populací imunosupresivních buněk. Imunologický profil HPV pozitivních, resp. HPV negativních nádorů v oblasti hlavy a krku přesto jednoznačně koreluje s terapeutickými výsledky a HPV specifická imunitní odpověď má pravděpodobně zásadní význam při lepší odpovědi HPV pozitivních pacientů na konvenční léčbu. Diskutujeme také vyvíjené postupy HPV specifické protinádorové imunoterapie, které jsou nyní ve fázi klinických zkoušek.
The insight into the biological nature of head and neck squamous cell carcinoma has evolved significantly in the last few years. Tobacco use and alcohol consumption are proven risk factors of head and neck squamous cell carcinoma. Cancer patients possessing such a tumor are generally elderly, mostly in fifth or sixth decade of life. In addition, significant association of head and neck squamous cell carcinoma with infection by human papillomavirus (HPV) was proven. HPV is now considered to be one of the most important risk factors, particularly for oropharyngeal carcinoma. HPV‑positive tumors of oropharynx are associated with significantly better prognosis. Experimental and clinical data indicate that HPV‑positive and HPV‑negative tumors can be considered as two different entities and it has not been clarified which factors are crucial for better prognosis of HPV‑positive tumors. The character of immune reaction, which contributes to distinct prognosis, may be one of the important factors. This review summarizes current knowledge concerning various aspects of anti‑tumor immune responses in HPV‑positive and HPV‑negative tumors. Recent studies have shown that a broad repertoire of tumor‑infiltrating HPV‑specific T-cells is detectable in almost all patients with HPV‑positive tumors. Despite this, there is a development of tumor, which may be facilitated by abnormalities in antigen processing, T-cell dysfunction or prevalence of immunosuppressive cells. Nonetheless, the immunologic profile of HPV‑positive vs. HPV‑negative head and neck squamous cell carcinoma is associated with better outcome, and HPV‑specific immune response is suggested to play an essential role in the better response to conventional therapy of HPV‑positive patients. We also discuss HPV‑specific antitumor immunotherapy approaches, which are now tested in clinical trials. Key words: head and neck cancer – human papillomavirus – immune system – T-lymphocytes – immunotherapy This study was supported by grant Internal Grant Agency of the Czech Ministry of Health No. NT 11542, FH Motol – grant No. 00064203 and by grants SVV 266513, UNCE 204013 and PRVOUK 27-1. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 31. 7. 2015 Accepted: 22. 8. 2015
- MeSH
- Adaptive Immunity MeSH
- Alphapapillomavirus immunology MeSH
- CD4-Positive T-Lymphocytes immunology MeSH
- CD8-Positive T-Lymphocytes immunology MeSH
- Immune System Phenomena * MeSH
- Immunotherapy methods MeSH
- Papillomavirus Infections * immunology complications MeSH
- Humans MeSH
- Human papillomavirus 16 immunology MeSH
- Biomarkers, Tumor immunology MeSH
- Head and Neck Neoplasms * genetics immunology therapy MeSH
- Oropharyngeal Neoplasms genetics immunology therapy MeSH
- Prognosis MeSH
- T-Lymphocytes, Regulatory immunology MeSH
- Carcinoma, Squamous Cell genetics immunology therapy MeSH
- T-Lymphocytes immunology MeSH
- Lymphocytes, Tumor-Infiltrating immunology MeSH
- Tumor Escape immunology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
Human papillomavirus (HPV) infection is one of the most important etiologic causes of oropharyngeal head and neck squamous cell carcinoma (HNSCC). Patients with HPV-positive HNSCC were reported to have a better clinical outcome than patients with HPV-negative cancers. However, little is known about the possible causes of different clinical outcomes. In this study, we analyzed a detailed immune profile of tumor samples from HNSCC patients with respect to their HPV status. We analyzed the characteristics of immune cell infiltrates, including the frequency and distribution of antigen-presenting cells and naïve, regulatory and effector T cells and the cytokine and chemokine levels in tumor tissue. There was a profound difference in the extent and characteristics of intratumoral immune cell infiltrates in HNSCC patients based on their HPV status. In contrast to HPV-negative tumor tissues, HPV-positive tumor samples showed significantly higher numbers of infiltrating IFNγ+ CD8+ T lymphocytes, IL-17+ CD8+ T lymphocytes, myeloid dendritic cells and proinflammatory chemokines. Furthermore, HPV-positive tumors had significantly lower expression of Cox-2 mRNA and higher expression of PD1 mRNA compared to HPV-negative tumors. The presence of a high level of intratumoral immune cell infiltrates might play a crucial role in the significantly better response of HPV-positive patients to standard therapy and their favorable clinical outcome. Furthermore, characterization of the HNSCC immune profile might be a valuable prognostic tool in addition to HPV status and might help identify novel targets for therapeutic strategies, including cancer immunotherapy.
- MeSH
- Programmed Cell Death 1 Receptor * MeSH
- CD8-Positive T-Lymphocytes * immunology MeSH
- Squamous Cell Carcinoma of Head and Neck * etiology immunology MeSH
- Papillomavirus Infections * immunology MeSH
- Humans MeSH
- Head and Neck Neoplasms MeSH
- Lymphocytes, Tumor-Infiltrating MeSH
- Check Tag
- Humans MeSH
